The purpose of this project is to determine the molecular basis of vulnerability of neurons to Alzheimer's disease (AD). An impairment in the molecular mechanism involving mitochondrial and nuclear genetic systems of oxidative phosphorylation (OXPHOS) is suggested for the reduced energy metabolism in AD. Brains from AD patients showed 50% decrease in levels of mRNA of mitochondrial DNA (mtDNA)-encoded as well as nuclear DNA (nDNA)- encoded genes of OXPHOS in an association neocortical region (mid-temporal cortex) known to be affected in AD, but not in the unaffected primary motor cortex, as compared to control brains. A rat model of chronic cytochrome oxidase inhibition, induced by continuous infusion of the inhibitor sodium azide, has been developed to test the hypothesis that impairment in energy metabolism would develop AD type neuropathology. Studies on the regulation of amyloid precursor protein (APP) in cell culture systems suggest that the induction of APP is essentially regulated by Ca2+. A modified immunological method - suppression in vivo followed by in vitro stimulation (SOFISTIC) - is developed to identify neuron specific molecules in the selectively vulnerable AD brain regions.